They cause substantial DNA damage in tumor cells, preventing tumor growth. Topotecan
has been evaluated in metastatic ovarian cancer. Irinotecan is a prodrug that is metabo-
lized to a topoisomerase I inhibitor; it has been used in the treatment of colon and
rectal cancer.
Podophyllotoxin Topoisomerase Inhibitors.Two compounds, etoposide (7.86) and
teniposide (7.87) are semisynthetic analogs of podophyllotoxin, a natural product extracted
from the root of the mayapple (Podophyllum peltatum). These compounds inhibit
topoisomerase II, causing DNA strand breakage, and have demonstrated bioactivity
in leukemia and lymphoma.
7.8.2 Drugs Interfering with Transcription and TranslationThe intercalating drugs and nucleic acid synthesis inhibitors discussed in the preceding
sections interfere indirectly with every phase of nucleic acid action because the DNA is
rendered nonfunctional. Other drugs, discussed below, affect the regulation of protein
synthesis even when the genome, the DNA structure, is intact. Such activity can be the
result of interference either with transcription of messenger RNA or with translation of
the mRNA to protein.
7.8.2.1 Natural Product Anti-Transcription Agents
Among the cytostatic agents in this group are the bleomycins, a very complex group of
natural product glycopeptides produced by Streptomyces verticillus. Among many bio-
chemical effects, bleomycins seem to cause the scission and breakage of DNA, render-
ing the process of transcription ultimately impossible. They also seem to inhibit DNA
ligase, an important DNA replication and repair enzyme. Bleomycin therefore inter-
feres with the transcription as well as replication of nucleic acids. Since there are no
bleomycin-degrading enzymes in the skin, squamous-cell carcinomas of the neck and
head respond well to this drug. However, toxic effects also prevail in skin tissue. The
unique activity and toxicity of the bleomycins can be utilized in the combination treatment
of malignancies, in which drugs with different modes of action and nonoverlapping
toxicities are used, often with remarkable success.
ENDOGENOUS CELLULAR STRUCTURES 453